Ropinirole is described in U.S. Pat. No. 4,452,808 as being useful in cardiovascular therapy and in U.S. Pat. No. 4,824,860 as an agent useful in treating Parkinson's disease. The processes for the preparation of Ropinirole HC 1 and its derivatives have previously been described. U.S. Pat. No. 4,452,808 describes the preparation of 4-aminoalkyl-2(3H)-indolones staring from either 4-aminoalkyl-7-hydroxy-2(3H)-indolones or 2-methyl-3-nitro-benzene acetic acid by two different processes. Particularly those processes involving reductive cyclization of nitrostyrene intermediates in presence of acetyl chloride and Iron (III) chloride described in EP 0300614 and WO 91/16306 are of particular relevance. Present invention discloses a novel route and novel intermediates for the preparation of Ropinirole. Present invention comprises of 6 steps leading to desired moiety.
U.S. patents namely U.S. Pat. No. 4,452,808, U.S. Pat. No. 5,336,781, U.S. Pat. No. 4,997,954, U.S. Pat. No. 4,314,944 molecule called Ropinirole. For the present purpose U.S. Pat. No. 4,452,808 and U.S. Pat. No. 4,314,944 are more relevant. Few patents deal with Ropinirole mainly from method of treatment point of view and therefore are not directly related to the present invention.
WO 91/16306 and EP 0300614 are relevant from the point of view of reductive cyclization and are dealt at appropriate place hereafter.
The processes for the preparation of Ropinirole HCl and its derivatives have previously been described. U.S. Pat. No. 4,452,808 describes the preparation of 4-aminoalkyl-2(3H)-indolones starting from either 4-aminoalkyl-7-hydroxy-2(3H)-indolones or 2-methyl-3-nitro-benzene acetic acid by two different processes. The 7-hydroxy intermediate (i) is first converted to its tetrazolo derivative (ii) which is then hydrogenated to get Ropinirole as shown in Scheme 1. Preparation of 7-hydroxy intermediate (i) is described in U.S. Pat. No. 4,314,944 by following a series of steps starting from p-methoxy phenethylamine. Second process described in U.S. Pat. No. 4,452,808 allows preparation of Ropinirole by following a series of steps starting from 2-methyl-3-nitro benzeneacetic acid.

Particularly those processes involving reductive cyclization of nitro styrene intermediates in presence of acetyl chloride and Iron (III) chloride described in EP 0300614 and WO 91/16306, are of relevance, as far as this invention is concerned.
Scheme 2 depicts the route disclosed in EP0300614. EP0300614 describes the preparation of Ropinirole by condensation of 4-[2-(bromoethyl)-1,3-dihydro-2H-indol-2-one (iii) with di-n-propyl amine (iv). The intermediate (iii) is prepared by following a series of steps starting from 2-(2-bromoethyl)benzaldehyde. Major drawback is a possible formation of an elimination product due to loss of HBr as shown in Scheme 2. Such reaction can impact the purity of desired product and can influence the yield aspects.
Elimination Product
The process as described in WO 91/16306 is an improved process for the preparation of Ropinirole comprising of number of steps, total of eight starting from Isochroman, to get the final product Ropinirole. It discloses the route wherein condensation of di-n-propylamine with a novel intermediate of formula (v) is carried out. Intermediate (v) is prepared by series of steps starting from Isochroman. The process involves well over 7 steps and therefore is a longer one.
